A peptide prodrug compound identified as G-202, and comprising the thapsigargin derivative 8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin (12ADT) linked to the aspartic acid of a peptide having the sequence Asp-Glu*Glu*Glu*Glu, wherein at least one of the bonds designated with * is a gamma carboxy linkage and having the structural formula:
(Formula 1) has been set forth and described in U.S. Pat. Nos. 7,767,648 and 7,468,354, which are incorporated herein in their entireties. Injectable cancer compositions comprising G-202 and Methods and Compositions for Treating Hepatocellular Carcinoma using G-202 are also disclosed in U.S. Provisional Appln. No. 61/714,662 and, 61/693,273, which are incorporated herein in their entireties.
The major challenge for a process to produce G-202 is due to the lack of crystallinity of any of the intermediates or final active pharmaceutical ingredient (API). This precludes the use of crystallization for removal of impurities at any point in the synthesis. This constraint makes it essential that the reactions be highly efficient and generate little to no impurities. In addition, the lack of crystallinity increases the value of alternate purification processes such as aqueous extractions, polar/non-polar organic partitioning, precipitation, trituration and efficient chromatographic purification. This process disclosed herein successfully incorporates an effective synthetic strategy and all of these purification techniques to generate pure G-202.